Prospective isolation and characterization of genetically and functionally distinct AML subclones

Bauke de Boer, Janine Prick, Maurien G Pruis, Peter Keane, Maria Rosaria Imperato, Jennifer Jaques, Annet Z Brouwers-Vos, Shanna M Hogeling, Carolien M Woolthuis, Marije T Nijk, Arjan Diepstra, Sebastian Wandinger, Matthias Versele, Ricardo M Attar, Peter N Cockerill, Gerwin Huls, Edo Vellenga, André B Mulder, Constanze Bonifer, Jan Jacob Schuringa

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28 Citations (Scopus)
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Abstract

Intra-tumor heterogeneity caused by clonal evolution is a major problem in cancer treatment. To address this problem, we performed label-free quantitative proteomics on primary acute myeloid leukemia (AML) samples. We identified 50 leukemia-enriched plasma membrane proteins enabling the prospective isolation of genetically distinct subclones from individual AML patients. Subclones differed in their regulatory phenotype, drug sensitivity, growth, and engraftment behavior, as determined by RNA sequencing, DNase I hypersensitive site mapping, transcription factor occupancy analysis, in vitro culture, and xenograft transplantation. Finally, we show that these markers can be used to identify and longitudinally track distinct leukemic clones in patients in routine diagnostics. Our study describes a strategy for a major improvement in stratifying cancer diagnosis and treatment.

Original languageEnglish
Pages (from-to)674-689.e8
Number of pages24
JournalCancer Cell
Volume34
Issue number4
Early online date20 Sep 2018
DOIs
Publication statusPublished - 8 Oct 2018

Keywords

  • acute myeloid leukemia (AML)
  • clonal heterogeneity
  • plasma membrane (PM)
  • proteome
  • genetically distinct subclones
  • DNase I hypersensitive site (DHS)
  • digital footprinting
  • FLT3-ITD
  • WT1
  • NRAS

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